This study supports prior preliminary evidence that DHEA supplementation reduces aneuploidy in women with DOR, first suggested in a small pilot study, when at least one euploid embryo was found significantly more frequently after DHEA than in matched control cycles . Subsequently, we also demonstrated that DHEA supplementation reduces miscarriage rates to a degree that cannot be explained without significant contribution from reduced aneuploidy .
By demonstrating no difference in embryo grades between DHEA and control cycles (Table 1), this study also demonstrates, once more, that embryo morphology, as currently routinely assessed in most IVF laboratories, does not reflect on embryo ploidy and, therefore, is limited in clinical value.
Since a majority of miscarriages are believed to be consequence of aneuploidy , decreases in aneuploidy rate should translate into decreases in spontaneous pregnancy loss. Two infertility centers utilizing DHEA supplementation, one in New York City and the other in Toronto, Canada, indeed, independently, reported identically low miscarriage rates of 15.0 and 15.2 percent, respectively. Depending on method of statistical analysis, these miscarriage rates represented declines of approximately 50 to 80 percent from expectations . Even more remarkably, the combined loss rate of 15.1 percent equated rates reported for normal populations as young as 28 to 33 years , and was, thus, far removed from excessively high miscarriage rates, reported in DOR patients .
Even though such significant declines in spontaneous miscarriages cannot be achieved without underlying improvements in aneuploidy, miscarriage rates only represent surrogates for true aneuploidy studies. Direct evidence for such an effect was, therefore, still needed.
In this study we for the first time are able to demonstrate such direct evidence, utilizing routinely performed PGS of preimplantation stage embryos, performed in DHEA supplemented IVF cycles and controls. DHEA supplementation was, indeed, associated with significantly reduced aneuploidy, and greatest reductions were observed with short DHEA supplementation of up to 12 weeks.
This observation on first impulse suggests that, excluding month one of supplementation, second and third months offer the best chance of lowering aneuploidy, thus fully supporting previously published pregnancy data after DHEA supplementation, which demonstrated a significant first rise in pregnancy rate after approximately six weeks of DHEA supplementation . Six weeks of DHEA supplementation prior to IVF cycle start, therefore, currently represents minimal supplementation time at our center.
This study, however, does not preclude, as alternative explanation for these findings that a more favorable patient group conceives quickly and, therefore, statistically distorts above noted time associations. Such a possibility cannot be ruled out since we previously demonstrated that women who improve AMH levels with DHEA supplementation demonstrate significantly superior pregnancy rates to those who do not .
A general criticism of currently available technologies for PGS is that only limited numbers of chromosomes can be evaluated (24 chromosome screening technologies are currently under investigation). In this study this meant that only seven chromosomes were assessed in study and control patients. This allows for the at least theoretical possibility that untested chromosomes demonstrate statistically different aneuploidy distributions from the here tested seven and that, including a full chromosome complement, here reported differences would disappear. Such an explanation is, however, highly unlikely, and the here utilized selection of chromosomes, or similar ones, have been routinely used in clinical PGS [15, 16]. There is also no data in either human or animal literature to suggest that DOR maybe associated with aneuploidy of specific chromosomes.
Because of time pressures, when using their own oocytes, prospectively randomized clinical trials in patient populations affected by DOR, and involving placebo, are difficult, if not impossible, to conduct. Our center, for that reason, had to abandon two registered clinical DHEA trials, one in the United States and one in Europe, due to lack of enrollment . A small first such trial has just been reported . Best available evidence, therefore, at least in part, has to be obtained via other study formats.
In this study, the format chosen was a case control study in which each study patient/cycle was matched with two controls. As Table 1 demonstrates, patient and control populations appear, with few exceptions, overall comparable. It is, however, important to point out that the significantly larger preponderance of DOR in the study group (Table 1) biases study results against discovery of DHEA effects on ploidy since DOR patients demonstrate the highest aneuploidy rate amongst infertility patients . Even just absence of increased aneuploidy in the study group could, therefore, be viewed as a potentially positive DHEA effect. Instead, this study actually demonstrates significantly lower aneuploidy following DHEA supplementation.
How DHEA affects non-dysfunctional events remains to be determined but we have speculated that DHEA supplementation may improve the ovarian environment in which follicular maturation takes place in older women [19 and submitted]. DHEA, indeed, significantly declines with advancing age . Since DHEA, except in our prior pilot study , has never before been directly associated with decreases in aneuploidy, neither animal nor human data are currently available to speculate further on specific mechanisms that may be involved.
Others have speculated that drugs can be developed which beneficially affect non-dysjunctional events during meiosis . DHEA may, indeed, turn out to be a first pharmacologic agent to do so.
This effect, only unlikely, should be restricted to infertile women with DOR. DHEA supplementation, in attempts to reduce embryo aneuploidy and spontaneous miscarriages, therefore, also deserves investigation in, especially older (above age 35 years) fertile women, attempting conception. A possible similar beneficial impact in fertile patient populations, attempting spontaneous conception, could have a major impact on public health by speeding up time to pregnancy and by reducing embryo aneuploidy and miscarriage rates.